Pulmonary vascular injury, which alters cellular dynamics and fluid transport properties, is a primary event leading to the development of edema in Adult Respiratory Distress Syndrome. The overall objective of this proposed interdisciplinary project (Biochemistry, Immunology, and Physiology) is to understand key pathophysiologic mechanisms of edematous lung injury by directly measuring the effect of altered microvascular pressure, membrane surface area, and vascular permeability. Experiments are designed to gain quantitative information on the effect that free radicals, key vasoactive mediators, and activated neutrophils have on transvascular fluid and protein flux in the early phase of edematous lung injury. The investigation will test the following hypothesis: that vasoactive mediators alter transvascular flux by selectively increasing pressure, while free radicals preferentially increase membrane permeability. To test our hypothesis we plan to use a unique combination of proven techniques to concomitantly measure mean microvascular pressure (double occlusion method), filtration surface area (direct microscopic observation), and capillary permeability (indicator dilution method) in the isolated perfused rat lung model. The importance of the research is three-fold. First, this investigation will provide new quantitative information about key mechanisms involved in the pathogenesis of vascular injury which is a major cause leading Adult Respiratory Distress Syndrome. Second, these studies provide proved new information on the mechanisms-of-action of activated neutrophils, free radicals, and vasoactive mediators by pinpointing their effects on microvascular pressure, membrane surface area, and capillary permeability. Third, our studies will identify early markers associated with the pathophysiologic processes of pulmonary edema formation. The latter is of particular importance since information gained from these studies will permit explorations of new therapeutic approaches in the treatment and prevention of pulmonary edema.